Exercising with a robotic exoskeleton can improve memory and gait in people with Parkinson’s disease by facilitating progressive exercise intensity

People with Parkinson’s disease (PwPD) can benefit from progressive high-intensity exercise facilitated with a lower-extremity exoskeleton, but the mechanisms explaining these benefits are unknown. We explored the relationship between exercise intensity progression and memory and gait outcomes in PwPD who performed 8 weeks (2 × per week) of progressive exercise with and without a lower-extremity powered exoskeleton, as the planned exploratory endpoint analysis of an open-label, parallel, pilot randomized controlled trial. Adults 50–85 years old with a confirmed diagnosis of PD participated. Twenty-seven participants randomized to exercise with (Exo = 13) or without (Nxo = 14) the exoskeleton were included in this exploratory endpoint analysis. Detailed exercise logs were kept and actigraphy was used to measure activity count*min−1 (ACPM) during all exercise sessions. Only the Exo group were able to progressively increase their ACPM over the entire 8-week intervention, whereas the Nxo group plateaued after 4 weeks. Exercise intensity progression correlated with change in the memory sub-scale of the SCOPA-COG and change in gait endurance from the 6MWT, consistent with the prevailing hypotheses linking high-intensity interval exercise to improved muscle and brain function via angiogenic and neurotrophic mechanisms. Facilitating high-intensity exercise with advanced rehabilitation technology is warranted for improving memory and gait endurance in PwPD. Registration: ClinicalTrials.gov, NCT 03583879 (7/10/2018).

Despite the growing body of evidence [1][2][3][4][5][6] supporting exercise as a low-cost and accessible treatment to slow progression of motor and non-motor impairments in people with Parkinson's disease (PwPD), participation in exercise programs remains a challenge for PwPD [7][8][9][10] .High-intensity exercise in particular holds considerable promise as a breakthrough intervention for many health ailments [11][12][13][14][15] including Parkinson's disease 1,2 .Although the exercise-induced mechanisms that work to improve body and brain function are becoming better understood in animals and humans [16][17][18] , the biggest challenge is how to deliver high-intensity exercise interventions to people who can benefit from them but whose condition is a barrier to participating in them.
There are many reasons why PwPD may find it difficult to participate in high-intensity exercise interventions, such as deconditioning, fear of falling, low self-efficacy, low expectations, and decreased motivation 3,19,20 .Solutions are needed for facilitating the delivery of engaging, high-intensity exercise to reduce disability in PwPD 21 .Examples such as the Park-in-Shape trial 1 -a home-based, gamified, high-intensity aerobic exercise program, and the SPARX trial 2 -a high-intensity treadmill-based walking program, have both shown reduced disease progression on the UPDRS motor III subscale after 6 months of training compared to the control group, but no change in mobility and cognitive functioning was reported over the study period.
Robot-assisted gait training (RAGT) -using stationary treadmill-based robotic systems -offers another potential solution for facilitating gait training interventions in people with disability 22,23 .Although this approach allows for multiple training cycles with controlled levels of assistance, research thus far shows that functional gains are not superior to treadmill training [24][25][26][27][28][29] .It may be that this type of robot assisted therapy where the 1.Did the Exo group achieve a higher exercise intensity (ACPM) during the exercise sessions compared to the Nxo group? 2. Did the Exo group exceed a threshold of 1354 ACPM during exercise sessions proportionally more than the Nxo group? 3. Does progression in exercise intensity correlate with changes in memory and gait outcomes after 8 weeks of twice-weekly exercise?

Methods
The pilot RCT was registered prospectively at ClinicalTrials.gov(NCT 03583879, 7/10/2018).The study took place at the Assistive Technology Clinic (ATC), Baycrest Hospital, Toronto, Ontario, Canada, between Sept. 2018 and Oct. 2019, and was approved by all relevant Research Ethics Boards (Baycrest, Toronto, ON, and University of New Brunswick, Fredericton, NB).The study was conducted in accordance with the Declaration of Helsinki, and all participants provided signed informed consent prior to enrollment.Details of participants, recruitment, randomization, outcomes measures and interventions are available in the main outcomes paper 41 .

Assessments of memory and gait
For the present study, based on our preliminary evidence 41 , we focused on relationships between exercise intensity during the intervention and the observed change scores in the "Memory and Learning" sub-scale of the SCOPA-COG, and the 6MWT for gait endurance.Scales for Outcomes in Parkinson's-Cognition (SCOPA-COG) is a validated 10 task assessment for quantifying cognitive functioning in PwPD 43,44 .Domains include attention, memory, executive function, delayed recall and visuospatial impairment 45 .The "Memory and Learning" sub-scale has a range of 0-22, where higher scores indicate better cognitive functioning in the memory and learning domain.
The 6MWT (distance in meters) was used to evaluate gait function and endurance 46 , and has been reported as reliable and/or valid in many patient populations 47 .Participants completed the test along a 25 m walkway.The test was repeated three times, and the score was the average of three repetitions.For this test, higher scores (distance walked) indicate better gait endurance.

Actigraphy during intervention exercises
To date there is no accepted standard for assessing exercise intensity in a clinical setting during the interventions that are being administered.While indirect calorimetry is commonly employed in studies for objectively quantifying pre-post VO2 peak 1,48 , the cart and respirator would make it cumbersome to measure exercise intensity

Actigraphy data processing
After the conclusion of the study the raw files for the 27 participants with up to 16 sessions each were exported as activity count data to csv files and further processed with custom written Matlab algorithms to calculate activity counts per minute (ACPM) by summing the activity counts across the time interval of the session (with leading and trailing noise removed) and dividing by the total time in minutes.Consistent with the recommendation from Jeng et al. 42 we included only the vertical channel accelerations.ACPM data were further normalized to body mass (ACPM/kg) to account for the mass being moved (ie. the participants' mass plus the exoskeleton, if applicable).
In addition to actigraphy analysis, participants' exercise logs which contained the actual numbers of sets and intervals for each element of the intervention (Table 1) were transformed into a relative "Log intensity index" for the purpose of comparing how the exercise intervention was delivered to the two treatment groups.We first ranked by consensus all the exercise activities in the intervention by their expected level of vigor (see column 4 of Table 1), multiplied those ranks by the maximum number of minutes, repetitions and sets planned for each www.nature.com/scientificreports/activity, and summed these to arrive at a prescribed maximum score if the participant performed all activities as scheduled.The algorithm was then applied to each participants' actual session log data and total scores divided by the prescribed maximum score to arrive at an "index" representing the degree to which the participant achieved the planned dose of exercise in each session.Using the data in Table 1, the prescribed log intensity index was computed and is illustrated in Fig. 1.

Statistical analysis
To answer the first research question, intensity metrics derived from actigraphy and from the exercise log sheet data were reduced to biweekly averages (for display) and means for intervention intervals T1 and T2, which were then compared between the Exo and Nxo groups using a 2-tailed independent samples t-test.
To answer the second research question, a 2 × 2 Chi-square cross-tabulation analysis was used to compare the frequencies of sessions for Exo and Nxo groups where the participant exceeded the ACPM threshold of 1354 42 .
To answer the third research question, Pearson correlation analysis was conducted to test if there was any relationship between progression in exercise intensity (T2-T1 scores) and memory and gait change scores.
Descriptive statistics were used to describe the sample, which included age, sex, height and weight (as measured in the clinic), body mass index (BMI), Hoehn & Yahr PD disease stage (H&Y), and the Montreal Cognitive Assessment (MoCA).
All statistical analysis were conducted using SPSS (IBM Inc.), with significance set at α = 0.05.

Ethical approval and informed consent
The study was approved by research ethics boards of Baycrest Hospital, Toronto, Ontario (REB #18-24) and the University of New Brunswick, Fredericton, New Brunswick (REB #2018-136).All participants provided signed informed consent prior to enrollment in the study.
Memory and gait outcomes were analyzed in our main outcomes paper 41 across the three treatment groups (Exo, Nxo and Con).Here we show the analysis between just the two exercise groups included in this study (Exo vs Nxo).Memory sub-scale of the SCOPA-COG and 6MWT results are shown Table 3.There were no significant differences (p > 0.05) in baseline scores for either measure.Post-pre comparison showed that the Exo group had a significant improvement in memory score (p = 0.035) and 6MWT score (p < 0.001) compared to the Nxo group, consistent with our previous report that included the waitlist control (Con) group 41 .Also previously unreported Figure 1.Log intensity index derived from the exercise progression prescription for an ideal hypothetical example where all reps and sets are completed according to the progression schedule.T1 refers to the first half (0-4 weeks) of the intervention which is the progression phase, and T2 refers to the last half (5-8 weeks) of the intervention which is the maintenance phase.Question 1: Did the Exo group achieve a higher exercise intensity (ACPM) during the exercise sessions compared to the Nxo group?
Log intensity index from log sheet data (Fig. 3a left) shows that participants in both groups progressed similarly, from about 50% to approximately 75% of the maximal prescribed intensity (ie.no. of reps and duration, etc.).
Comparison of the progression from T1 and T2 (Fig. 3a right) between the groups likewise shows that both advanced the same in terms of increasing their sessional activities as prescribed (p > 0.05).
In contrast, the actigraphy data (Fig. 3b left) shows that although participants were progressing similarly in prescribed sessional intensity, the activity count rate for the Exo group continued to increase for each bi-weekly interval, whereas exercise intensity for the Nxo group remained relatively unchanged during the trial.Comparison of the progression from T1 and T2 (Fig. 3b right) between the groups shows that Exo group increased their exercise intensity significantly (p = 0.01) compared to the Nxo group.As indicated by Fig. 3b (left), only the Exo group's mean exceeded an exercise intensity above the cut-point threshold of 1354 ACPM, during the T2 period.Analysis of the sessional data showed that in 83 of the 180 total sessions (46%) received by the Exo group, and 64 of the 190 total sessions (34%) received by the Nxo group, participants exceeded the 1354 ACPM threshold during their session.Chi-square analysis showed a significant difference in these proportions (p = 0.015) where the Exo group had a higher-than-expected number of sessions that exceeded the 1354 ACPM threshold while the Nxo group had a lower-than-expected number of sessions that exceeded the threshold.

Question 3: Does progression in exercise intensity (T2-T1) correlate with changes in memory and gait outcomes after 8 weeks of twice-weekly exercise?
Figure 4 shows correlation analysis results of SCOPA-COG memory and 6MWT change scores versus the change in body mass normalized exercise intensity achieved between T1 and T2 of the intervention as measured by actigraphy.Change in exercise intensity between T1 and T2 correlated significantly with change in 6MWT scores and (r = 0.612, p = 0.004) and change in SCOPA-COG memory score (r = 0.388, p = 0.050).
Given the significant correlations between change scores in 6MWT and the memory sub-scale of the SCOPA-COG, an ad-hoc partial correlation analysis was conducted to test if the change in exercise intensity was driving this relationship.The partial correlation between 6MWT and SCOPA-COG memory when controlling for ACPM/kg remained significant (r = 0.597, p = 0.007), meaning that exercise intensity did not explain this effect.

Discussion
The main objective of this paper was to explore the relationship between exercise intensity and memory and gait outcomes in PwPD who participated in 8 weeks (2 × per week) of progressive functional exercise with and without a lower extremity powered exoskeleton, with the goal of providing a plausible mechanistic explanation for the improvement in memory and gait endurance in the group that exercised with the exoskeleton device, compared to the group that exercised without the exoskeleton 41 .
We demonstrated that PwPD, who have moderate levels of disability, and exercised with the exoskeleton, can feasibly achieve high-intensity exercise (exceed 1354 ACPM) after a relatively short (4 weeks) progression period, and can continue to increase their intensity for at least another 4 weeks, as illustrated in Fig. 3. Achieving those levels of intensity were less frequent with the group that did not wear the exoskeleton, whose intensity levels tended to plateau at moderate-intensity levels.Importantly, our preliminary evidence also suggests that these effects can translate into improvement in important rehabilitation outcomes-memory and gait-which, as illustrated in Figs. 2 and 4, are interconnected.The implications of our findings, and the potential actions they warrant, will next be discussed.PwPD beyond what is achievable using the treadmill alone or other forms of manual gait training therapies for neurological conditions [24][25][26][27][28] .Why then would an overground exoskeleton be expected to yield results different from a stationary one?If we consider the multi-system integration required for independent human overground locomotion, compared to being walked in a body weight supporting and laterally constraining mechanical apparatus, the nonbody weight supporting overground exoskeleton (ie.does not support vertical load) should stress the biological system in ways the stationary robot cannot, which may elicit neurophysiological responses more appropriate for triggering the cascade of mechanisms that can lead to improved muscle and brain function [16][17][18] .Our data suggests that exercising with an overground, non-bodyweight supporting, exoskeleton may facilitate achieving this goal by providing movement stability while preserving the need to work against gravity 53 .Because our actigraphy analysis focused on the vertical acceleration counts, we can conclude that participants wearing the device were able to increase their intensity of anti-gravity movements during the exercises, compared to those who exercised without the device.
Our data also show that these effects were not immediate, indicating that one month of progression was required before users of the exoskeleton were able to start achieving consistent exercise intensity levels defined (for the PD population) as "high-intensity".To elaborate, Fig. 3b (left) provides some key observations of how the participants in our study responded to the two different modes of exercise delivery.During the progression (T1) phase of the intervention both groups exercised at similar sub-threshold intensity levels, and in fact the Nxo group had slightly better (though non-significant) levels of intensity.Participants in the Exo group would have been learning how the exoskeleton interacts with them.After the 4-week progression period (during T2), only the Exo group was able to continue to increase their exercise intensity level.Indeed, the slope of the bi-weekly intensity curve would suggest that, had the intervention been longer, the Exo participants may have continued to increase their levels of intensity beyond the 8-week period.
Indeed, the difference between T2 and T1 mean exercise intensities (in this case, monthly estimates) appeared to be an important indicator of benefits gained from the intervention.Data in Fig. 4 suggests that increasing exercise intensity between the T2 and T1 periods explained about 37% of the variance in 6MWT change scores, and about 15% of the variance in SCOPA-COG memory and learning change scores, when all exercising participants were included.Figure 4 also shows that members of the Exo group appear more frequently in the upper-right quadrant of the scatter plots, again illustrating that wearing the exoskeleton during the exercise interventions had an impact on trial outcomes.
Interestingly, although there was clearly a strong relationship between the 6MWT distance and SCOPA-COG memory and learning change scores, and both were related to T2-T1 ACPM change in exercise intensity, the partial correlation test failed: the relationship observed between change in gait endurance and change in cognition was not moderated by exercise intensity level.This suggests that mobility and cognition are linked via other neurophysiological mechanisms-ie. the mechanism exists despite exercise or exoskeletons-but that exercising at a sufficiently high intensity allows that mechanism to be exploited.In other words, the intensity of the exercise progression determines to some degree where one is positioned on the regression line in Fig. 2. What this means to practice is that it may not be the exoskeleton itself that is explaining the beneficial mechanisms at play, but what the exoskeleton facilitates (ie.novel learning experience plus high intensity interval training) that may be of particular importance to its place in rehabilitation.
More detailed dosing studies are needed that include traditional metabolics, blood biomarkers, and brain imaging, to properly discern how this, and possibly other rehabilitation technologies, interact with proangiogenic and neurotrophic mechanisms that are known to improve muscle and brain function.The role of learning to https://doi.org/10.1038/s41598-024-54200-ywww.nature.com/scientificreports/ was a significant correlation between the 6MWT and SCOPA-COG memory change scores (r = 0.675, p = 0.001) across the sample of participants in the active exercise interventions (Exo and Nxo), as shown by the overlay scatter plot in Fig.2.

Figure 2 .
Figure 2. Overlay scatter plot showing the relationship between change in gait endurance as measured by the 6-min walk test (6MWT) and change in memory as measured by the SCOPA-Cog Memory and Learning subscale.Light blue boxes represent participants who exercised without the exoskeleton (Nxo) and the dark blue circles represent the participants who exercised with the exoskeleton (Exo).Vertical and horizontal dashed lines demark the zero-change lines.

Figure 3 .
Figure 3. Exercise dose measured two ways: (a) Log intensity index showing how well participants were on average able to progress according to the ideal prescription.;and (b) Mean activity counts per minute (ACPM) from actigraphy shows how intensely participants were on average able to exercise during the interventions.The left panels show the results averaged over 2-week intervals and the panels on the right show the mean difference between T1 and T2 phases.

Figure 4 .
Figure 4. Scatter plots showing the relationship between body mass normalized change in exercise intensity (ACPM/kg) between T1 and T2 phases, with change in gait endurance from 6-min walk test (6MWT) (left panel) and change in SCOPA-Cog Memory and Learning sub-scale score (right panel).Light blue boxes represent participants who exercised without the exoskeleton (Nxo) and the dark blue circles represent the participants who exercised with the exoskeleton (Exo).Vertical and horizontal dashed lines demark the zerochange lines.

Table 1 .
Exercise program used in the intervention.HIIT High intensity interval training, PNF D2 Proprioceptive neuromuscular facilitation, "draw sword" shoulder extension.

Table 2 .
Participants in the exploratory study.Exo Exoskeleton exercise training, Nxo Exercise training without exoskeleton, BMI Body mass index, MoCA Montreal Cognitive Assessment, H&Y Hoehn & Yahr PD disease stage.